Clinical Researcher—August 2020 (Volume 34, Issue 7)

FORM & FUNCTION

Alison Holland

The ancient Greek philosopher Plato was light-years ahead of his time when he said: “Necessity is the mother of invention.” Hundreds of years later, this maxim still applies, as the COVID-19 pandemic is driving extraordinary inventiveness, including in terms of how researchers are conducting virtual or decentralized clinical trials (DCTs).

Background

DCTs are not a brand new idea. For more than a decade, the drug and medical device development industry has been trying to answer the question: How do we bring the study to the patient? DCTs offered a potential answer, yet companies had been wary to adopt this previously relatively untried model. Now, bringing trials to patients is no longer a nice-to-have, as more than half of the top 50 pharmaceutical companies have had to make protocol changes in their ongoing trials since the pandemic began and others have paused trials completely. As of May 20, one-third of sponsors were switching to virtual or decentralized models, according to the Tufts Center for the Study of Drug Development (CSDD).{1}

SIDEBAR: How Do Decentralized Clinical Trials (DCTs) Work?

DCTs leverage technology to treat study patients remotely and through hybrid models that often include minimal in-person visits. Inclusion of digital technologies varies by study, but can include eConsent, telemedicine, wearable devices, electronic clinical outcome assessments (eCOAs), and electronic health (eHealth) records, to name a few. Mobile technologies are often used as electronic diaries and to collect data from wearable sensor devices. Home health nursing or devices shipped to patients allow the performance of assessments such as blood pressure, ECG, and phlebotomy services within the patient’s home. This model improves patient centricity by reducing the burden on study participants while leveraging technology to enable quality doctor/patient interactions.

Part of the industry’s reluctance to adopt DCTs was due to the unknowns around how to safely care for patients and reliably collect data remotely. Further, with regulators’ increased requirements for a risk-based approach to trial management, conservative life sciences companies were barely dipping their toes in the water, limiting experience to small pilot projects.

Fortunately, organizations are establishing new DCT best practices for safety and reliability, and reviewing their internal standard operating procedures and processes to fit into the DCT study design. Additionally, cloud-based platforms are emerging to create a superhighway for patient study data—aggregating all sources, from wearable devices to local lab visits, in real time—enabling real-world evidence strategies to be followed.

Partnerships between technology providers, sites, and labs, too, enable a seamless path to partially or fully DCTs that put patients first and follow a risk-based approach. Now, once-timid biotechs are jumping fully into the DCT ocean and seeing the benefits—more accurate data, increased patient recruitment, better patient engagement, and faster trial execution, to name just a few.

It’s unlikely that companies will ever revert to traditional models. By 2022, nearly two-thirds of active physicians are expected to start using telemedicine.{2} Aiding in the adoption are new safety guidelines from the U.S. Food and Drug Administration (FDA);{3} meanwhile, the Centers for Medicare and Medicaid Services relaxed its reimbursement rates for telemedicine visits, according to the Trump Administration.{4}

Long after the pandemic subsides, companies will recall these dark days and want to be prepared to minimize the risk of trials being disrupted again. Five key steps will help them successfully decentralize in-flight trials and start new DCTs within a risk-based framework.

Five Steps to Guide Successful Risk-Based DCTs

1. Document a specific decentralized study design and implementation plan, including all patient safety, data integrity, and regulatory considerations (see Figure 1).
2. Determine the wearables and devices that are needed, what tools are already being used in the study ecosystem (i.e., interactive response technology, electronic data capture, central labs, etc.), and other types of support that would be needed (i.e., home health nursing, local labs, etc.).
3. Evaluate how decentralized data will be reviewed and monitored to ensure quality and integrity. For example, define which data are collected for remote patient safety oversight monitoring and which for study endpoint analysis.
4. Equip all sites for success in a decentralized model, considering how it will impact efficiency and daily operations. Map out the options that would be best for each site, including those that are available within a site’s infrastructure already, to leverage different technologies or remote support teams. Additionally, consider what support and training will be needed to enable the sites to engage effectively in DCTs.
5. Enhance the patient/physician relationship in a virtual world by providing options such that study teams, investigators, and patients have choices about how they can participate in a study. It’s important to recognize that one size does not fit all, so flexibility is crucial to allow for physician and patient choice in order for DCTs to be efficient and effective for both parties.

Figure 1: Patient Safety, Data Integrity, and Regulatory Considerations for DCTs

Protocol risk assessment

• Patient safety risk
• Investigational medical product (and comparator) availability and accessibility to patient
• Primary endpoint availability (can this be collected digitally?)
• Timelines and length of study
• Enabling care of existing patients and/or new patient enrollment

Deployment risk assessment

• Geographic spread
• Timelines for priority patient engagement
• Local country logistics (on the ground travel/accessibility)
• Local regulations and institutional review board recommendations
• Device usability
• Data privacy considerations
• Site staff availability (and location)
• Contracting and quality assessment status

Mitigation activities

• Pragmatic scoping to rapidly deploy generic televisit for investigator/patient connectivity
• Comprehensive project plan for roles and responsibilities to meet deployment goals and timelines (medical, study, site, patient, quality assurance, contracting, information technology, data management)
• Accelerated change management
• Real-time communication
• Training and site/patient support

Patient Safety: The North Star for Assessing Risk

Every study has a risk management plan, but regulations now require evidence that it is being followed, adjusted, and evolving with the study. Patient safety is the north star of risk assessment for every trial, and especially for DCTs. Eighty-eight percent of clinical trial sponsors surveyed by Medable report that patient safety is paramount when considering a DCT.{5} For example, during the COVID-19 health crisis, the first risk-assessment question to determine the feasibility of a DCT has become “is it safer to continue dosing patients remotely or safer to stop dosing altogether?” If continued dosing is the safer option, the risk assessment for a DCT continues.

Transitioning in-flight studies to a decentralized model overnight presents the most complicated case for ongoing, safe conduct of a trial. Study leaders need to consider whether safe dosing requires other health checks, such as blood pressure monitoring and vital signs. Then, they need to decide how to accurately measure these factors digitally and/or remotely.

The answer to each question triggers a new set of questions, such as how do you deploy digital measurement devices? How will you train patients or caregivers to use them correctly? Are they available to everyone in the study? How long until you can get the device? A week versus a month or a year? Answers to these questions and more assure patient safety when switching to a DCT.

The second major focus for risk assessment is data integrity. Again, risk factors must be addressed, including patient privacy, accurate data capture, real-time data flow, and reliable reporting. Also to be considered are broader issues regarding data comparability to previously collected data and the impact of data analysis plans on the study.

Transformative Value for Sites, Sponsors, and Patients

There are many advantages to DCTs—even beyond solving many of the problems of recent, pandemic-driven stay-at-home mandates. For example, a DCT model can significantly reduce time spent documenting outcomes, collecting data, and transitioning patients through in-person visits. This opens more time for investigator staff to spend more quality time with patients.

DCTs also extend access to trials for patients who have travel restrictions, can’t manage an onsite visit schedule/frequency, or are geographically distant. In fact, 93% of surveyed physicians using telehealth say it improves access.{2} “Using digital technologies to bring clinical trials to the patient, rather than always requiring the patient to travel to the investigator, is an FDA priority,” said former FDA Commissioner Scott Gottlieb, MD, in March 2019.

Overall, DCTs significantly improve trial efficiency and execution—a top priority for sponsors and contract research organizations. From increasing participant diversity and speeding patient enrollment to improving data quality and increasing patient retention, DCTs can trim the fat from slow-moving trials that benefit sites, sponsors, and especially patients.

Increased Site Capacity for Additional Studies

The total number of endpoints in a single clinical trial rose 86% from 2008 to 2018, according to the Tufts CSDD, making the burden on sites almost unbearable.{6} Digitizing study processes with tools such as eCOA, electronic/remote informed consent, and electronic patient-reported outcomes allow patients to complete study tasks at home that would typically be performed at the site and frees investigator staff from redundant data entry.

Expanded Trial Access and Diversity of Participants

Distance, travel, and participant diversity have long been challenges in recruitment and in developing therapeutics that are generalizable to the population. DCTs allow patients to participate in clinical research from where they are, removing the barriers of travel and geography to accelerate enrollment, increase retention, and add diversity.

The National Center for Biotechnology Information (NCBI) found that a decentralized model recruited three times as many patients as the traditional model and did so three times faster.{7} The patients in the decentralized model also better represented urban and rural areas, whereas the traditional model only consisted of those living near an existing clinical trial site.

These benefits apply to trials across all disease states, but are particularly important for rare diseases, as trials for these are few and far between and participants may be spread across wide geographic areas. Patients are often willing to travel for an initial assessment and final visit—the bookends of their trial experience—but need to maintain their day-to-day life without the burden of frequent site visits, which is only possible in a decentralized model.

Improved Data Robustness and Accuracy

The apps, wearables, and other technologies deployed in DCTs directly track study compliance and patient symptoms, providing more oversight of adherence and enhanced patient safety monitoring. These tools automatically collect data continuously for greater accuracy because they are not reliant on patients to remember or even document many aspects of their study experiences. This also means DCTs can deliver data from the source, eliminating second-hand data sources and reducing the need for transcription verification.

DCTs can also provide insights about how the interventions affect patients’ daily lives (real-world evidence). For example, perhaps a medication is suspected of causing an immediate but short-term side effect. If the patient is able to self-administer during his or her regular daily activity, a wearable can record a change in heart rate, respiration, and other data points, providing a physician with real-time visibility of the symptoms rather than waiting for the patient to report them at the next scheduled visit.

If needed, an ad hoc televisit with the patient can be used to record and/or rule out an adverse event and reassure the patient, thus helping prevent a dropout while contributing real-time, real-world evidence to the study.

Improved Patient Engagement and Retention

DCTs decrease participant burden (e.g., travel costs, time off work or away from family), which makes study participation more attractive to patients and caregivers. Fewer visits are especially important for patients with limited mobility, who are working full-time, who are caregivers, or who juggling the time demands of a young family. Investigators strive to support patient recruitment, however sometimes the study burden is off-putting to patients. Further, since two-thirds of investigator sites fail to meet patient enrollment requirements, it is particularly important to take advantage of methods proven to accelerate trial attractiveness and execution.

Bringing the trial to the patient not only accelerates study recruitment times, it minimizes dropouts. The NCBI study mentioned previously showed the trial retention rates were 89% for the decentralized model and only 60% for the traditional model.{7} Enhanced retention is driven, too, by the constant “at a click” connection that patients have with their doctor and staff. DCTs offer choices and facilitate connections that provide patients with assurances and physicians with confidence that the patient is safe.

Expedited Patient Identification and Cost Reduction

Patient identification and outreach have always been significant drivers of the costs and inefficiencies of research. In a recent longitudinal study targeting a rare genetic variant of dry age-related macular degeneration, more than 8,000 participants needed to be identified, pre-consented, and screened. Traditional methods would have limited the pool to those living near specific sites and required patients to travel, making it difficult to recruit an adequate number of qualified patients in a reasonable timeframe.

However, leveraging DCT technology, patients were pre-screened at home, enabling the sponsor to reach underrepresented populations, speeding patient enrollment, and improving participant data capture. The decentralized approach reduced the patient enrolment cycle time and costs by $20 million.{5}

DCTs are Proving Themselves as a Successful Invention That’s Here to Stay

From the largest to the emerging, life sciences companies are embracing DCTs, and so are their partners and patients. A recent Site Landscape Survey by the Society for Clinical Research Sites revealed that more than half of sites reported they would do “whatever is required” to conduct a virtual or decentralized trial, while 75% of patients say that collecting all study data from their own home is appealing.{8}

Clinical research, wherever it occurs, will always require the expertise and experience of qualified teams that embrace a risk-based approach. By implementing a “patient first” DCT, organizations can shatter the traditional study paradigm and finally achieve sought-after improvements in patient accessibility, unification of data, and data availability, culminating in faster, more effective trials.

We have the ability to engage with our patients, learn about their lives and priorities, and apply these insights to optimize the study design and mitigate upfront risks. For example, by employing technology to conduct pre-recruitment assessment data collection, companies can understand how people live so that protocols can be customized—bringing a patient-focused experience to clinical research.

While the COVID-19 pandemic has been a catalyst in forcing new clinical trial execution models to go mainstream, they will be part of a mix of options in the long term. The advantages are powerful and the results are the proof—DCTs are here to stay.

References

1. CenterWatch. 2020. Pandemic Unleashes Momentous Change in Clinical Research. See full resource here.
2. American Well. 2020. Telehealth Index: 2019 Physician Survey. See full resource here.
3. FDA.gov. How is the FDA Advancing Digital Health. See full resource here.
4. Centers for Medicare and Medicaid Services. 2020. President Trump Expands Telehealth Benefits for Medicare Beneficiaries. See full resource here.
5. Medable. 2020. Survey of 150 Clinical Trial Sponsors.
6. Tufts Center for the Study of Drug Development. 2018. Rising Protocol Complexity is Hindering Study Performance, Cost, and Efficiency. CSDD Impact Reports. See full resource here.
7. National Center for Biotechnology Information (NCBI). 2018. Building Clinical Trials Around Patients: Evaluation and comparison of decentralized and conventional site models in patients with lower back pain. See full resource here.
8. Center for Information and Study on Clinical Research Participation (CISCRP). 2019. 2019 Perceptions and Insights Study: Patient Experience Report. See full resource here.

Alison Holland (aholland@medable.com) is Head of Virtual Clinical Trials at Medable. She has more than 30 years of clinical trial experience, most recently as Global Vice President and General Manager for General Medicine at Covance.